CXCR2 is a well-characterized G-protein coupled receptor for a number of chemokines that share the Glu-Leu-Arg (ELR) motif including interleukin-8 (IL-8, CXCL8) and growth regulated oncogene alpha, beta and gamma, (GROα,β,γ or CXCL1,2,3) that are known to be involved in the recruitment of neutrophils to a site of injury [Reutershan, J. (2006) Drug News Perspect 19:615-623]. CXCR2 is expressed primarily on neutrophils (PMN), but can be expressed on other leukocytes as well such as monocytes. Antagonism of CXCR2 has been shown to be effective in blocking the recruitment of PMN to the lung in response to stimuli such as LPS, cigarette smoke, or ozone exposure both preclinically and in humans [Thatcher T H (2005) Am Jour Phys Lung Cell Mol Phys 289:L322-L328; Reutershan J (2006) J Clin Invest 116:695-702]. Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P, Tsai M, Sadeh J, Magnussen H. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur Respir J 2010; 35:564-570 Lazaar A L, Sweeney L E, MacDonald A J, Alexis N E, Chen C, Tal-Singer R. SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans. Br. J. Clin. Pharmacol. 72:282-293 (2011) Selective antagonism of the interaction between CXCR2 and its various chemokine ligands provides a potential strategy for reducing the underlying inflammation that contributes to the progression of multiple diseases [Chapman R W, Phillipsa J E, Hipkina R W, Currana A K, Lundella D and Fine J S. CXCR2 antagonists for the treatment of pulmonary disease. Pharmacol. Ther. 2009; 121(1): 55-68. as demonstrated in preliminary studies in patients with respiratory diseases (Nair P, Gaga M, Zervas E, Alagha K, Hargreave F E, O'Byrne P M, Stryszak P, Gann L, Sadeh J, Chanez P; Study Investigators. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 2012; 42:1097-2103) Rennard S I, Dale D C, Donohure J F, Kanniess F, Magnussen H, Sutherland E R, Watz H, Lu S, Stryszak P, Rosenberg E, Staudinger H. CXCR2 antagonist MK-7123—a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 187:A6071.
The CXC chemokines that possess the ELR motif (e.g., CXCL1/GROα, CXCL8/IL-8) are important in the recruitment of inflammatory cells that mediates pathology in multiple organ settings. Pathology is related, for example, to inappropriately released hydrolytic enzymes and reactive oxygen species from activated neutrophils. On the other hand, during most bacterial infections this chemokine response represents a critical first line of defense, but even here ELR+ CXC chemokine responses can, via their abilities to activate inflammatory cells displaying the CXCR1 and CXCR2 receptors, exacerbate the pathology. Despite the critical importance of these chemokine responses in many settings, inflammatory cell responses are sufficiently damaging that identification of therapeutic tools to block ELR+ chemokines is of interest.
The ELR chemokines chemoattract and activate inflammatory cells via their CXCR1 and CXCR2 receptors. The CXCR1 is specific for CXCL8 and CXCL6, while the CXCR2 binds CXCL8 with high affinity, but also binds CXCL1, CXCL5 and CXCL6 with somewhat lower affinities. CXCL8 signaling in cell lines transfected with the human CXCR1 or CXCR2 induces equipotent chemotactic responses. Neutrophil cytosolic free Ca++ changes and cellular degranulation in response to CXCL8 are also mediated by both receptors, but the respiratory burst and activation of phospholipase D reportedly depend exclusively on CXCR1. On the other hand, it has been reported that a non-peptide antagonist of CXCR2, but not CXCR1, antagonizes CXCL8-mediated neutrophil chemotaxis, but not cellular activation. Finally, there is abundant evidence that chemokines are most often redundantly expressed during inflammatory responses.
WO 2007/124424 discloses compounds useful in the treatment of disease states mediated by IL-8, including the compound N-{4-chloro-2-hydroxy-3-[3-piperidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea, and the enantiomer N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl) urea.
There remains a need for treatment, in this field, for compounds which are capable of antagonising CXCR2.